The primary objective for this proposal is to examine a novel approach to improve immune reconstitution (IR) when antiretroviral therapy (ART) is begun in HIV infected persons. This is significant because few individuals achieve normal immunity with current ART and up to 20% people with complete viral suppression have little or no increase in CD4+ T cell counts. Even among those with partial normalization of CD4+ T cell counts in peripheral blood, lymphoid tissues (LT) remain depleted by as much as 50%. This observation may explain persistent defects in immune function among people treated with antiretroviral therapy including poor vaccine responsiveness, increased bacterial infections, and poor control of mucosal pathogens like human papilloma virus and herpes simplex virus. Further, the increasing incidence of non-AIDS related cancer deaths from colon or lung cancer and non-AIDS associated lymphoma among HIV+ persons treated with ARV highlight the need for adjunctive therapies to improve immune function. Recently we described a process of fibrosis in lymphatic tissues of HIV infected persons that destroys critical structures of the paracortical T cell zone (TZ) of secondary lymphatic tissues important for antigen presentation and T cell homeostasis. The degree to which the TZ becomes fibrotic is indirectly and significantly correlated to the size of the CD4+ T cell population in lymphatic tissues and the magnitude of CD4+ T cell reconstitution in peripheral blood when ART is begun. In our preliminary data we demonstrate in a non-human primate model of SIV infection that antifibrotic therapy with pirfenidone, a drug used for the treatment of idiopathic pulmonary fibrosis, limits collagen formation in the TZ and enhances preservation of CD4 T cell populations. We hypothesize that therapies directed at limiting or reversing pathologic fibrosis in LT will restore critical anatomical elements of the TZ which, in turn, will lead to significantly greater CD4+ T cell numbers and function. In this proposal we will use the non-human primate model of SIV induced lymphatic fibrosis that we have developed to determine if antifibrotic therapy given as adjunctive therapy with ART can reverse existing fibrosis and improve immune reconstitution. We will intervene with pirfenidone, with and without ART, at 12 weeks post-infection, a time that approximates chronic infection in humans when ART would be considered. We will measure changes in levels of collagen in LT, changes in CD4+ T cell populations in peripheral blood and lymph node, and functional assessments of immunity with primary and recall responses to antigens. We anticipate finding that ART with pirfenidone will result in a significantly larger CD4+ T cell population and improved immune function than when ART is used alone. PUBLIC HEALTH RELEVANCE: This project will evaluate therapies for HIV infection that may improve the ability of currently available anti-retroviral therapy to improve immune function. We will test a novel strategy to restore normal anatomy to lymph nodes that might allow more normal sized populations of CD4+ T cells to reconstitute. This has relevance to public health as HIV infection is a significant cause of morbidity and mortality world-wide and current therapies do not fully restore immune function.